Ribonuclease A is one of the simplest and most thoroughly characterized enzyme and is chosen as the focus for the high accuracy electronic structure study proposed here. The potential energy surface for the catalytic reaction and the protein-nucleic acid interactions leading to base recognition will be investigated. The proposed research is to be carried out in close collaboration with semisynthesis efforts to identify the catalytic and base recognition roles of specific active site residues and to test computationally proposed redesigned enzymes. Collaboration with RNase biomimetic synthesis efforts is also planned. Selectivity and rate changes resulting from computationally predicted model modifications will be tested experimentally. Detailed understanding of the catalysis in RNase will aid in constructing and evaluating mechanistic hypotheses for more complex enzymes and in adaptation of biochemical principles to chemical usage. RNase serves as one of the most accessible models for studying protein-nucleic acid interactions and knowledge gained here will elucidate processes occurring in replication, transcription and translation. Enzyme redesign has important applications in diverse areas such as defense against viral RNA and providing new reagents for sequencing RNA. State-of-the-art electronic structure methods will be employed: ab initio molecular orbital solutions with an extended, polarized basis set augmented by correlation corrections from configuration interaction or Moller-Plesset perturbation theory. A modified conjugate gradient method or a constrained simplex optimization procedure is to be used in the search for transition structures and determination of minimum energy paths.